HMNC Brain Health announced positive topline results from its OLIVE trial, a randomized, double-blind, placebo-controlled Phase 2b study evaluating BH-200 (nelivaptan) in patients with Major Depressive Disorder (MDD). The trial demonstrated clinically meaningful efficacy across the full study population while revealing particularly strong responses in a genetically defined patient subgroup.
Trial Design and Patient Population
The OLIVE trial enrolled 338 patients with MDD across eight countries in Europe between May 2023 and April 2025. Patients were randomized in a 2:1 ratio to receive BH-200 (250 mg twice daily) or placebo for eight weeks. The modified intention-to-treat population comprised 331 patients, with 295 completing the study.
BH-200 is a highly selective vasopressin V1b receptor antagonist that had previously demonstrated efficacy in a Phase 2 trial with 319 patients. The primary endpoint was defined as mean HAM-D17 total score change from baseline to Week 8 in one of three subgroups classified by HMNC's proprietary genetic selection tool.
Efficacy Results Across Patient Population
The study demonstrated that BH-200 led to a clinically meaningful reduction in depressive symptoms across the full patient population. The difference between BH-200 and placebo in HAM-D17 change from baseline at Week 8 was -2.98 (SE = 0.82; p = 0.0003; Cohen's d effect size = 0.44).
Treatment separation from placebo emerged at Week 4 (p < 0.05) and increased over time, demonstrating sustained efficacy throughout the eight-week treatment period.
Genetic Subgroup Analysis Reveals Enhanced Efficacy
A central innovation in the OLIVE study was HMNC's proprietary genetic selection tool, which classifies patients based on biomarkers linked to vasopressin signaling and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The tool classified patients into three biologically distinct subgroups based on vasopressin-related biology.
Subgroup A, comprising 89 patients (27% of the study population), showed the greatest clinical benefit with a difference between BH-200 and placebo in HAM-D17 change from baseline at Week 8 of -4.47 (SE 1.58; p = 0.005; Cohen's d effect size = 0.55). This subgroup demonstrated rapid improvement with separation from placebo as early as Week 1 (p = 0.027) and maintained superiority at every subsequent assessment.
On the Montgomery-Åsberg Depression Rating Scale (MADRS), Subgroup A showed a mean difference versus placebo of -5.95 (SE 1.81, p = 0.002) at Week 8.
The data revealed a biologically consistent gradient of response across the three genetic profiles: Subgroup A (-4.47; p = 0.005), Subgroup B (-2.85; p = 0.037), and Subgroup C (-1.94; p = 0.153).
Safety Profile
BH-200 was generally safe and well tolerated. The most common treatment-emergent adverse event was headache, reported in 8.9% of patients receiving BH-200. Three serious adverse events—allergic purpura, pneumonia, and acute stress—were reported in two patients, all occurring in the placebo group.
Asymptomatic and transient elevations in liver aminotransferase enzymes (AST or ALT > 3x ULN) were observed in 5.8% of patients in the BH-200 group, with all cases resolving without clinical consequence. HMNC is exploring biomarker-based approaches to identify potential predictive indicators of liver enzyme elevations.
Expert Commentary and Clinical Significance
"The OLIVE trial results confirm earlier clinical trial data, validating vasopressin modulation as a novel and viable treatment approach in depression," said Hans Eriksson, MD, PhD, MBA, Chief Medical Officer of HMNC. "Interestingly, the pre-defined patient Subgroup A showed a clinically robust response beginning at Week 1, highlighting the power of our genetic selection tool to identify those most likely to benefit."
Professor Florian Holsboer, former director of the Max Planck Institute of Psychiatry and HMNC co-founder, commented: "The central role of vasopressin in the neurobiology of depression inspired the development of BH-200, a selective V1b receptor antagonist. In a large, controlled clinical trial, we were able to clearly demonstrate that a genetics-guided selection tool can identify the patient population that responds most favorably when this novel mechanism is targeted."
Alan F. Schatzberg, MD, Professor of Psychiatry and Behavioral Sciences at Stanford University, noted: "We've long understood the relevance of the HPA-axis in stress-related depression, but this is the first time we've seen clear improvement in MDD through vasopressin modulation. This could represent a paradigm shift toward more biologically informed treatment decisions in psychiatry."
Development Pipeline and Next Steps
HMNC Brain Health will initiate regulatory discussions for Phase 3 development of BH-200, leveraging its proprietary genetic selection tool. The company reports having results from two large randomized trials with more than 600 patients—one in the U.S. and one in Europe—both showing clinically meaningful improvement in MDD.
HMNC's pipeline includes three Phase 2 programs in MDD: Nelivabon (vasopressin V1b receptor antagonist with genetic selection tool), Cortibon (CRHR1 antagonist with matching genetic selection tool), and KET01 (prolonged-release oral ketamine formulation for at-home treatment).
The findings establish first-in-class potential for an HPA-axis modulator in depression treatment and support the potential of precision psychiatry approaches in moving beyond trial-and-error prescribing toward more targeted therapeutic interventions.
